Zhao Yueshui, Gu Xue, Zhang Ningyan, Kolonin Mikhail G, An Zhiqiang, Sun Kai
Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas; and.
Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas.
Am J Physiol Endocrinol Metab. 2016 Dec 1;311(6):E952-E963. doi: 10.1152/ajpendo.00314.2016. Epub 2016 Oct 11.
Endotrophin is a cleavage product of collagen 6 (Col6) in adipose tissue (AT). Previously, we demonstrated that endotrophin serves as a costimulator to trigger fibrosis and inflammation within the unhealthy AT milieu. However, how endotrophin affects lipid storage and breakdown in AT and how different cell types in AT respond to endotrophin stimulation remain unknown. In the current study, by using a doxycycline-inducible mouse model, we observed significant upregulation of adipogenic genes in the white AT (WAT) of endotrophin transgenic mice. We further showed that the mice exhibited inhibited lipolysis and accelerated hypertrophy and hyperplasia in WAT. To investigate the effects of endotrophin in vitro, we incubated different cell types from AT with conditioned medium from endotrophin-overexpressing 293T cells. We found that endotrophin activated multiple pathological pathways in different cell types. Particularly in 3T3-L1 adipocytes, endotrophin triggered a fibrotic program by upregulating collagen genes and promoted abnormal lipid accumulation by downregulating hormone-sensitive lipolysis gene and decreasing HSL phosphorylation levels. In macrophages isolated from WAT, endotrophin stimulated higher expression of the collagen-linking enzyme lysyl oxidase and M1 proinflammatory marker genes. In the stromal vascular fraction isolated from WAT, endotrophin induced upregulation of both profibrotic and proinflammatory genes. In conclusion, our study provides a new perspective on the effect of endotrophin in abnormal lipid accumulation and a mechanistic insight into the roles played by adipocytes and a variety of other cell types in AT in shaping the unhealthy microenvironment upon endotrophin treatment.
内营养蛋白是脂肪组织（AT）中胶原蛋白6（Col6）的裂解产物。此前，我们证明内营养蛋白作为一种共刺激因子，在不健康的AT环境中引发纤维化和炎症。然而，内营养蛋白如何影响AT中的脂质储存和分解，以及AT中的不同细胞类型如何对内营养蛋白刺激作出反应仍不清楚。在当前研究中，通过使用强力霉素诱导的小鼠模型，我们观察到内营养蛋白转基因小鼠的白色脂肪组织（WAT）中脂肪生成基因显著上调。我们进一步表明，这些小鼠的WAT中脂解受到抑制，肥大和增生加速。为了研究内营养蛋白在体外的作用，我们将来自AT的不同细胞类型与过表达内营养蛋白的293T细胞的条件培养基一起孵育。我们发现内营养蛋白在不同细胞类型中激活了多种病理途径。特别是在3T3-L1脂肪细胞中，内营养蛋白通过上调胶原蛋白基因触发纤维化程序，并通过下调激素敏感性脂解基因和降低激素敏感性脂肪酶（HSL）磷酸化水平促进异常脂质积累。在从WAT分离的巨噬细胞中，内营养蛋白刺激胶原蛋白连接酶赖氨酰氧化酶和M1促炎标记基因的更高表达。在从WAT分离的基质血管部分中，内营养蛋白诱导促纤维化和促炎基因的上调。总之，我们的研究为内营养蛋白在异常脂质积累中的作用提供了新的视角，并深入了解了脂肪细胞和AT中多种其他细胞类型在内营养蛋白处理后塑造不健康微环境中所起的作用机制。
